XML Feed for RxPG News   Add RxPG News Headlines to My Yahoo!   Javascript Syndication for RxPG News

Research Health World General
 
  Home
 
 Latest Research
 Cancer
 Psychiatry
 Genetics
 Surgery
 Aging
 Ophthalmology
 Gynaecology
 Neurosciences
 Pharmacology
 Cardiology
 Obstetrics
 Infectious Diseases
 Respiratory Medicine
 Pathology
 Endocrinology
 Immunology
  Autoimmune Diseases
  Immunosupressants
  Monoclonal Antibodies
 Nephrology
 Gastroenterology
 Biotechnology
 Radiology
 Dermatology
 Microbiology
 Haematology
 Dental
 ENT
 Environment
 Embryology
 Orthopedics
 Metabolism
 Anaethesia
 Paediatrics
 Public Health
 Urology
 Musculoskeletal
 Clinical Trials
 Physiology
 Biochemistry
 Cytology
 Traumatology
 Rheumatology
 
 Medical News
 Health
 Opinion
 Healthcare
 Professionals
 Launch
 Awards & Prizes
 
 Careers
 Medical
 Nursing
 Dental
 
 Special Topics
 Euthanasia
 Ethics
 Evolution
 Odd Medical News
 Feature
 
 World News
 Tsunami
 Epidemics
 Climate
 Business
 
 India
Search

Last Updated: Nov 18, 2006 - 12:32:53 PM

Immunology Channel
subscribe to Immunology newsletter

Latest Research : Immunology

   DISCUSS   |   EMAIL   |   PRINT
Test Model Accounts for T Cells' Discriminating Ways
Oct 26, 2005 - 3:59:00 PM, Reviewed by: Dr.

T cells that showed this explosive response could also distinguish between pMHCs with minor differences in TCR binding time, reinforcing the importance of the SHP-1 negative feedback system in preventing “sneak-through activation” by non-agonists. (SHP-1 is a dephosphorylating enzyme.) To test this hypothesis in a quantitative manner, Altan-Bonnet and Germain constructed a TCR signaling model in which kinetic proofreading of TCR–ligand interactions produces a quick initial negative feedback response (mediated by SHP-1) and a delayed, explosive digital ERK positive feedback system that, once activated, overrides the negative pathway and allows productive signaling.

 
When a pathogen slips into the body, it might infect a cell or get eaten by a specialized white blood cell. Either way, its proteins get chopped into peptide fragments, loaded onto molecules encoded by genes in the major histocompatibility complex (MHC), and sent to the cell surface as a peptide-loaded MHC molecule (pMHC) for immune surveillance. The immune system can rally against billions of pathogens, in part because every T cell expresses a unique receptor (TCR), acquired during development, that recognizes specific pMHCs. Developing T cells undergo a selection process that weeds out more than 98% of cells, leaving only those cells whose receptors react to “self” pMHCs enough to signal but not enough to fully activate the T cells. Because antigen-presenting cells (APCs) in an infected host bear both self and pathogen-derived pMHCs, proper immune function depends on the discriminatory capacity of TCRs: they must allow a full T cell response to foreign antigens and avoid reacting to self-peptides on the same cell surface.

When a T cell homes in on a pathogenic antigen, the response is quick, sensitive (just a few molecules can set them off), and digital (all or nothing), engaging signaling pathways necessary for T cell activation, proliferation, and survival. (Molecules called agonist ligands trigger TCR signaling.) Signals relay through the cell as kinase enzymes activate proteins by triggering chemical reactions that add one or more phosphates (a process called phosphorylation); removing phosphates (called dephosphorylation) deactivates the proteins and the signal decays.

One explanation for this rapid, sensitive response is that pMHCs induce unique conformational changes in the receptor to initiate signaling. But a TCR can react differently to the same pMHCs at distinct points in its life history, and binding pairs show no conformations specific to agonists versus non-agonists. Alternately, in the kinetic proofreading concept, a kinetic threshold related to the TCR–pMHC binding properties accounts for ligand discrimination—though in simple forms of this hypothesis discrimination occurs at the expense of a rapid, sensitive, digital response.

Hoping to resolve these discrepancies, Grégoire Altan-Bonnet and Ronald Germain combined computer modeling with experimental results to develop a quantitative model of early TCR signaling. The authors revealed a novel aspect of TCR signaling—the explosive digital response of a key enzyme in the pathway—and identified competing feedback systems that may explain how T cells combine selectivity with a rapid, sensitive response.

To construct a predictive model, Altan-Bonnet and Germain measured kinetic aspects of biochemical responses to TCR–pMHC pairing by focusing on extracellular signal-related kinase (ERK), a key player in the TCR signaling cascade. Using T cells harvested from transgenic mice engineered to produce identical TCRs and APCs engineered to express very few self-pMHCs, the authors studied the conditions required for ERK activation. In individual T cells, the ERK pathway was activated by as few as ten foreign ligands. These experiments also revealed a “previously unappreciated aspect” of ERK signaling in T cells: it either occurred or it didn't, but when it did, the result was 100,000 phosphorylated ERK enzymes.

T cells that showed this explosive response could also distinguish between pMHCs with minor differences in TCR binding time, reinforcing the importance of the SHP-1 negative feedback system in preventing “sneak-through activation” by non-agonists. (SHP-1 is a dephosphorylating enzyme.) To test this hypothesis in a quantitative manner, Altan-Bonnet and Germain constructed a TCR signaling model in which kinetic proofreading of TCR–ligand interactions produces a quick initial negative feedback response (mediated by SHP-1) and a delayed, explosive digital ERK positive feedback system that, once activated, overrides the negative pathway and allows productive signaling. The authors then ran signaling simulations using different ligand numbers with different TCR binding lifetimes. Their model “shows almost absolute discrimination” between closely related pMHCs while preserving a fast, sensitive response to just a few agonist ligands.

The model also yielded predictions that the authors validated experimentally: the ERK response slows down dramatically at low ligand densities; negative feedback adjusts to ligand strength and quantity to prevent signaling by high concentrations of low-affinity ligands, and allows sensitive responses to low concentrations of high-affinity ligands; differential activation of the negative feedback explains the existence and hierarchy of antagonism in T cell activation; and mature differentiating T cells permit signaling with different levels of ligand discrimination, depending on intracellular concentrations of molecules such as SHP-1.

Altogether, these results suggest that ligand discrimination is not “hard-wired” into TCR–ligand structural affinities. Rather, the threshold that permits TCR signaling varies as concentrations and dynamics of intracellular molecules vary during T cell development and after antigen activation. The model described here, though a necessarily simplified version of TCR signaling, highlights the effectiveness of simple feedback loops in helping cells filter out unwanted signals while effecting quick, sensitive responses—properties crucial for most other regulatory networks. The model also reinforces the importance of detailed probing of cell signaling dynamics to better understand the functions of a living system. —Liza Gross
 

- (2005) Experimentally Validated Model Accounts for T Cells' Discriminating Ways. PLoS Biol 3(11): e391
 

Read Research Article (Open Access) at PLoS Journal Website

 
Subscribe to Immunology Newsletter
E-mail Address:

 

DOI: 10.1371/journal.pbio.0030391

Published: October 25, 2005

Copyright: © 2005 Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License

PLoS Biology is an open-access journal published by the nonprofit organization Public Library of Science.


Related Immunology News

Pregnant women with lupus are at higher risk for complications
Molecular 'signature' protects cells from viruses
Discovery in the evolution of the immune system absorbing cells
Leeds University study shows eculizumab may be an effective therapy for PNH
Research Reveals Inner Workings of Immune System �Thermostat�
CD23 Protein in Stool Samples may Indicate Food Allergy
Molecular signals triggering maturation of natural killer cells uncovered
New method to analyse the Major Histocompatibility Complex (MHC) of the human genome
Front Line Immune Cells Mature in Four Stages - Study
Caspase-12 gene that shuts down immune system is found in 20% of people of African descent


For any corrections of factual information, to contact the editors or to send any medical news or health news press releases, use feedback form

Top of Page

 

© Copyright 2004 onwards by RxPG Medical Solutions Private Limited
Contact Us